Nonprescription AC Meeting March 23, 2005

1. THE QUEST FOR CLINICAL BENEFIT Steven Osborne, M.D. Medical Officer Division of Over-The-Counter Drug Products Nonprescription AC Meeting March 23, 2005

2. Key Issues • Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?

3. Key Issues • Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?

4. Monograph Antiseptics • Alcohols (ETOH and IPA) • Purell Handrub • Chlorhexidine (CHG) 2% and 4% Aqueous • Hibiclens and Hibiprep • Iodine or Iodophors (PI) • Tincture of iodine and povidone-iodine (Betadine) • Triclosan • Gojo Antimicrobial Lotion Soap

5. Monograph Antiseptics • Quaternary Ammonium Compounds • Benzalkonium chloride (Zephiran) • Phenol Derivatives • Carbolic acid • Chloroxylenol (PCMX) • Triclocarban • Safeguard soap

6. Antiseptic Antimicrobial Spectrum (CDC 2002) Group Gram PositiveGram NegativeSpeed of Action Alcohols +++ +++ Fast Chlorhexidine +++ ++ Intermediate Iodine Compounds +++ +++ Intermediate Iodophors +++ +++ Intermediate Phenol Derivatives +++ + Intermediate Triclosan +++ ++ Intermediate Quaternary AC + ++ Slow +++ excellent, ++ good, but does not include entire bacterial spectrum, + fair

7. Citizen Petition And Comment • Industry Coalition--Soap and Detergent Association (SDA) and Cosmetic, Toiletry, and Fragrance Association (CTFA): Citizen Petition and Comment to the TFM • Submitted references • Requested FDA lower efficacy standards

8. Healthcare Procedures • Invasive Procedures: • Surgery • Catheters, IVs • Non-Invasive procedures • Reduce nosocomial infections with handwash • Reduce respiratory and GI illness with handwash

9. Antiseptics References • Industry Coalition: Citizen Petition and Comment to the TFM: • 155 Articles and Abstracts • 58% HW, 26% PP, 16% SS • Weight of evidence of clinical benefit not persuasive for changing current efficacy criteria • No link between surrogate endpoints and infection rates

10. Summary Of Study Limitations • Surrogate endpoints not correlated with clinical outcome • Not randomized • No placebo control • Retrospective • Multiple confounders • Inadequately powered • No statistics • Lack of standardization of product use • Irregular patterns of data collection • Failure to address a TFM indication

11. Study Examples • Maki et al. 1991 (catheter infections) • Luby et al. 2002 (impetigo)

12. Maki et al 1991 • Randomized study in 668 subjects with IV catheters • all catheters CV or arterial • 2% CHG, 10% PI, 70% IPA • then every other day. No other agents applied

13. Maki et al 1991 • Endpoints: • Local infection rate (>15 CFUs) • 2.3% for CHG, vs 7.1% (alcohol) and 9.1% (PI), P=0.02 • Bacteremia • 10 total • CHG (1), alcohol (3), PI (6), P=0.18

14. Maki et al 1991 • No correlation between reduction in bacteria with infection rates • Application of antimicrobial post- catheter insertion limits ability to relate to monograph application

15. Luby et al 2002 • Double blind, randomized study of antibacterial soap in 241 households in Karachi, Pakistan • Triclocarban soap, bland soap, standard practice group • Primary outcome was incidence of impetigo

16. Luby et al 2002 • Triclocarban soap 43% less impetigo than standard practice (P=0.02) • Triclocarban 23% less impetigo than than bland soap (P=0.28) • Bland soap 24% less impetigo than standard practice (P=0.21) • Needed 70% increase in sample size

17. SURGICAL SCRUBS • Surgical hand scrubs • 300 articles screened for clinical benefit • None conclusively linked reduction in bacteria with reduction in infection rates

18. Study Examples • Bryce et al 2001 • 70% IPA leave-on • in-use hospital evaluation • 70 scrubs by surgeons • 15 ml product used over 3 min • Endpoint: post-op bacterial counts • IPA agent comparable to 4% CHG and 7.5% PI in reducing bacteria • No infection rates studied

19. Study Examples • Parienti et al. 2002 • Hand-rubbing with alcoholic leave-on solution and 30-day surgical site infection (SSI) rate • Randomized, crossover equivalence trial (75% alcohol, 4% PI, 4% CHG) • 6 surgical services, 4287 pts

20. Parienti et al. 2002 • Alcohol hand-rub, PI and CHG as hand-scrub • SSI 2.44% alcohol vs. 2.48% with PI+CHG • Scrub time compliance better with alcohol rub (313 sec vs 287 sec, P=0.01) • SSI micro not provided • Surgeon not blinded (reported SSI)

21. HANDWASH Literature Review • Literature review of healthcare personnel Handwashes 1994-2004 • 222 studies reviewed for clinical benefit or efficacy • None showed a definitive link between bacterial reduction and reduction in infection rates

22. HANDWASH References • Swoboda et al. 2004, 3-Phase, 15 month evaluation incorporating an electronic monitor (monitor, voice-prompt, monitor) • Compliance improved by 35%, 41% in Phase 2 and 3 • MRSA or VRE colonization rates 19%, 9%, 11%

23. Patient PREOP Literature Review • 400 articles screened • Searched for bacterial log reduction data post-scrub compared with pre-scrub, then ….. • Searched for SSI rate in same reference

24. Patient PREOP Literature Review • Majority of studies performed in animals • None of the studies found link between colony forming units (CFU) of bacteria and SSIs

25. Patient PREOP Literature Review • Secondary topic: Is there a minimum number of bacteria in a wound that predisposes to infection? • 100,000 bacteria (105) • May vary with type of bacteria

26. Patient PREOP Literature Review • 100,000 bacteria “threshold” for infection • Kass 1957: • 2000 patients with pyelonephritis had >100,000 • 100% of symptomatic patients with UTI had >100,000 • Krizek et al. 1967 • 94% graft success when pre-graft bacteria <100,000/ gram tissue

27. Study Literature • Cronquist et al. 2001 • 609 neurosurgery patients • Craniotomy • Ventriculo-Peritoneal (VP) shunt • Pre-scrub and post-scrub bacterial counts from head, back

28. Cronquist et al. 2001 • Bacterial counts (log10):

29. Study Literature • Cronquist et al. 2001 • 20 SSIs • 19 from craniotomies • Staph species, P. acnes • No correlation between pre-scrub or post scrub counts and SSIs

30. Key Issues • Do Clinical Trials Assessing Infection Rates Provide Definitive Evidence Of Clinical Benefit?

31. Key Issues • Does the Clinical Evidence Link Surrogate Endpoints With Clinical Benefit?